Nickel-Catalyzed Reductive Cross-Coupling Reactions For The Synthesis And Modification Of Natural Products

Transition-metal-catalyzed cross-coupling reactions provide a powerful tool for the construction of carbon-carbon bonds for the synthesis or modification of complex molecules. In the first chapter, the development history and current status of transition-metal-catalyzed reductive coupling reactions (direct cross-coupling between two electrophiles) has been reviewed, in which Nickel-catalyzed reductive cross-coupling reactions are particularly introduced. Nickel-catalyzed reductive cross-coupling reactions have been developed as practical strategies for the construction of carbon-carbon bonds with excellent functional group compatibility and well developed reaction mechanism. The development of novel reductive cross-coupling reactions, by means of utilizing the nature of Nickel catalyst for the activation of C(sp3) centers, would complement traditional carbon-carbon forming reactions and partly overcome the problems in traditional cross-coupling reactions based on the use of alkylmetallic reagents and alkyl halides.Nickel-catalyzed reductive cross-coupling reactions, which have excellent cross-coupling selectivity and functional group compatibility, are suitable for the construction of carbon-carbon bonds for complex molecules. In the second chapter, we developed a mild reaction condition employing Nickel-catalyzed reductive cross-coupling reactions for the expedient synthesis of non-natural amino acids. Through the reductive coupling of serine/homo-serine derived iodides with aryl/acyl/alkyl halides, L- or D-amino acids are rapidly synthesized with retention of the absolute configuration at a-carbon.Olefins are among the most important synthons in organic synthetic chemistry which are readily available and inexpensive. The olefin groups are also widely existed in natural products which have complex structures as well as numerous functional groups. In the third chapter, we developed an example of Nickel-catalyzed reductive olefin hydrocarbonation reaction. The presented reaction utilized the olefins as direct input for the construction of carbon-carbon bonds which complements the traditional cross-coupling reactions based on the using of alkylmetallic reagents. Our new reaction has good functional group compatibility, large number of synthetic valuable functional groups could be tolerated and thus provides an effective way for the late modification of complex molecules.In the third chapter, we discovered that Nickel could realize the hydroalkylation of un-activated olefins with alkyl halides. This surprising finding prompted us to further develop a more practical approach which could avoid the using of alkyl halides. In the fourth chapter, we developed Nickel-catalyzed reductive decarboxylative olefin hydroalkylation reaction for the construction of C(.sp3)-C(sp3) bonds which employs the decarboxylative cross-coupling of NHPI-esters with un-activated olefins. This reaction provides an efficient method for the convergent modification of complex molecules which contain olefin groups and carboxylic acid groups.By using ’Nickel-Bpy-Reductant’ catalytic system, we have realized a series of reductive cross-coupling reactions on the C(sp3) centers. And these works preliminarily solved some difficult problems in traditional cross-coupling reactions, especially the source and handling of alkylmetallic reagents and alkyl halides. Furthermore, we also expanded the concept and scope of Nickel-catalyzed reductive cross-coupling reactions. However, challenges remain, for example, the construction of quaternary carbon center as well as stereo-chemical control etc. Efforts will be devoted to overcome these difficulties.